Author(s): Stein CM, Murray JJ, Wood AJ
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Abstract BACKGROUND: Prediction of cyclosporine (CSA) efficacy and toxicity in individual patients is difficult. There is no practical, biologically relevant, pharmacodynamic measure of CSA effect. A major effect of CSA is to decrease interleukin-2 (IL-2) production; however, measurement of this effect in isolated lymphocytes as a marker of response to CSA has been problematic. METHODS: CSA inhibition of phytohemagglutinin-P (PHA)-stimulated IL-2 production, measured by ELISA, was studied ex vivo in whole blood drawn before, and after subjects received 4 mg/kg oral CSA. RESULTS: Four hours after CSA was administered, the mean (+/- SD) CSA concentration was 702 +/- 196 microg/L and PHA-stimulated IL-2 production decreased by 68.7\% +/- 17.2\% (P <0.0001; n = 17). Twenty-four hours after CSA was administered, concentrations were low (64 +/- 24 microg/L), with no inhibition of IL-2 production. A rapid, concentration-dependent response occurred. Maximum CSA concentrations (944 +/- 187 microg/L) and maximum inhibition of IL-2 production (86.9\% +/- 13.7\%) occurred 90 min after subjects received CSA. In vitro, 32.5-1200 microg/L CSA also inhibited PHA-stimulated IL-2 production in whole blood in a dose-dependent fashion with a similar IC(50) (approximately 300-400 microg/L) ex vivo and in vitro. CONCLUSION: In the search for a pharmacodynamic marker to better guide immunosuppressive therapy, the relationship between this simple, biologically relevant measure of CSA effect and clinical outcome should be determined.
This article was published in Clin Chem
and referenced in Journal of Clinical Toxicology